Abstract

Background: Schizophrenia is a complex neuropsychiatric disorder of unclear etiology. The strongest known genetic risk factor is the 22q11.2 microdeletion. Research has yet to confirm which genes within the deletion region are implicated in schizophrenia. The minimal 1.5 megabase deletion contains MIR185, which encodes microRNA 185.

Methods: We determined miR-185 expression in embryonic and adult mouse brains. Common and rare variants at this locus were then investigated using a human genetics approach. First, we performed gene-based analyses for MIR185 common variants and target genes using Psychiatric Genomics Consortium genome-wide association data. Second, MIR185 was resequenced in German patients (n = 1000) and controls (n = 500). We followed up promising variants by genotyping an additional European sample (patients, n = 3598; controls, n = 4082).

Conclusion: Human genetic analyses generated no evidence of the involvement of MIR185 in schizophrenia. However, the expression patterns of miR-185 and its target genes in mice, and the genetic association results for the 3 target genes, suggest that further research into the involvement of miR-185 and its downstream pathways in schizophrenia is warranted.

Acknowledgements: We are grateful to all of the patients and control individuals who contributed to this study. We also thank the probands from the Heinz Nixdorf Recall (HNR) study. We thank Marie Luise Dreisow and Peter Tessmann for their excellent technical assistance. We also thank Christine Schmäl for her careful reading of the manuscript. We are grateful to the Psychiatric Genomics Consortium for contributing to this study by sharing of their data. We confirm that these data will be used for noncommercial research purposes only. We have complied with all applicable state, local and federal laws or regulations and institutional policies regarding human subjects and genetic research. We acknowledge that secondary distribution of the data without registration by secondary parties is prohibited and confirm that we will cite the appropriate PGC publication in any communications or publications arising directly or indirectly from these data.

Funding: This study was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to M.M. Nöthen and S. Cichon; grant 01GS08147 to M. Rietschel), under the auspices of the National Genome Research Network plus (NGFNplus). M.M. Nöthen is a member of the DFG-funded Excellence-Cluster ImmunoSensation. M.M. Nöthen also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. A.J. Forstner received support from the BONFOR program of the Medical Faculty of the University of Bonn. This study was partially supported by a grant from the European Union (EUTwinsS network; RTN, FP6), which supported work in which F.B. Basmanav was a Marie Curie Fellow and M.M. Nöthen and S. Cichon were principal investigators. The HNR cohort was established with the support of the Heinz Nixdorf Foundation. These funding sources had no involvement in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication.

Competing interests: A.D. Børglum is the co-founder and CEO of PsychoGenetics, which pursues strategies for new diagnostic and therapeutic approaches for mental disorders.